Benzamidoalkylbenzenesulfonamidopyrimidines and analogues thereof



United States Patent 3,377,351 BENZAMIDOALKYLBENZENESULFONAMIDO-PYRIMIDINES AND ANALUGUES THEREOF Erich Haack, Heidelberg, Ruth Heerdt,Mannheim, Felix H. Schmidt, Mannheim-Nenostheim, Kurt Stach, Mannheim,and Rudi Weyer, Frankfurt am Main-Unterliederbach, Germany, assignors toC. F. Boehringer & Soehne G.m.b.H., Mannheim-Waltlhof, Germany, acorporation of Germany No Drawing. Continuation-impart of applicationSer. No. 455,295, May 12, 1965. This application Sept. 23, 1966, Ser.No. 581,445 Claims priority, application Germany, May 20, 1964, B76,848; Oct. 9, 1965, B 84,050 11 Claims. (Cl. 260256.5)

ABSTRACT OF THE DISCLOSURE A novel class of2-benzene-sulfonamido-pyrimidines is disclosed. The said compoundsconstitute highly effective antidiabetic agents and the invention asdisclosed includes antidiabetic compositions as well as a method forcarrying out antidiabetic therapy. The Z-benzene-sulfonamido-pyrimidineshave the following formula:

wherein X is alkylene containing 1 to 4 carbon atoms, A is substitutedor unsubstituted alkyl, cycloalkyl, aryl, aralkyl, arylmercaptoalkyl oraryloxyalkyl, R is substituted or unsubstituted alkyl, cycloalkyl, aryl,aralkyl, alkoxy, alkoxyalkyl or alkoxyalkoxy and R is hydrogen, loweralkyl or substituted or unsubstituted aralkyl.

This application is a continuation-in-part of application Ser. No.455,295, filed May 12, 1965, now abandoned.

This invention relates to novel Z-benzene-sulfonamidopyrimidines andmore particularly relates to novel 2-benzene-sulfonamide-pyrimidines andto anti-diabetic compositions containing said novel compounds.

Substituted 2-benzene-sulfonamido-pyrimidines having a blood sugarreducing action have been described in German patent specification No.1,147,948, British patent specifications Nos. 913,716 and 939,608, andBelgian patent specifications Nos. 609,270; 622,085, and 622,086.

A primary object of the present invention is the development of a newseries of therapeutically useful chemical compounds.

A further object of this invention is the development more particularlyof a new group of chemical compounds characterized by antidiabeticactivity.

A still further object of this invention is the development of a newseries of therapeutically useful new chemical compounds capable ofreducing blood sugar for a considerable period of time without anyincidence of undesirable side effects.

These and other objects and advantages will be apparent from thedescription and claims which follow:

The novel 2-benzene sulfonamido-pyrimidine compounds of this inventionare represented by the following structural formula:

wherein X represents a straight or branched chain hydrocarbon radicalcontaining 1 to 4 carbon atoms, A represents an unsubstituted orsubstituted alkyl, cycloalkyl, aryl, aralkyl, arylmercaptoalkyl oraryloxyalkyl radical, R is an unsubstituted or substituted alkyl,cycloalkyl,

aryl, aralkyl, alkoxy, alkoxyalkyl or alkoxyalkoxy radical, and R ishydrogen lower alkyl or an unsubstituted or substituted aralkyl radical.

A preferred group of compounds are represented by the following formula:

(a) Reaction of compounds of the formula:

AC O1TIX R2 )uC1 wherein A, R and X have the afore-indicated meaningsand n is 0, 1 or 2, with Z-amino-pyrimidines of the wherein R has theabove indicated meaning, and the products obtained oxidized, ifnecessary, to the corresponding sulfonamides;

(b) Reaction of benzene-sulfonyl-guanidincs of the formula:

A-CONX NH R2 SO2-NH-C\ NH: (IV) wherein A, R and X have the aboveindicated meanings, with compounds of the formula:

Y-O ooH ooY' l iii (V) wherein R is as above defined and Y and Y eachrepresents hydrogen or an alkoxy radical, or with a functionalderivative thereof, andthereafter converting the pyrimidine derivative'thus produced, which may be substituted in the 4- and/or 6-position byhydroxyl groups, into the corresponding pyrimidine derivative which areunsubstituted in the 4- and 6-positions by first forming the halogencompounds and then subjecting this to a reductive dehalogenation;

(0) Acylation of compounds of the formula:

R2NH X I I N. V

SMH a N (v1) wherein X, R and R are as above defined, with a reactivederivative of an acid of the formula A-COOH, wherein A has theafore-indicatedmeaning;

(d) Reaction of sulfonamides of the formula:

'(VIII) wherein A, R and X are as above defined, with2-acetylaminopyrimidines of the formula:

wherein R has the above indicated meaning.

The reaction of compounds (II) and (III) is advantageously carried outin an inert solvent in the presence of a base, preferably pyridine ortrimethylamine. However, it is also possible to carry out the reactionwith a double excess of the amino-pyrimidine in order to bind thehydrogen chloride formed by the reaction. The subsequent oxidation ofthe sulfenamides or sulfinamides to the desired sulfonamides is carriedout in the usual manner, for example, by treatment with hydrogenperoxide, potassium permanganate or nitric acid.

The benzene-sulfonyl-guanidines (IV) used as starting materials can beobtained, for example, by melting together the appropriatebenzene-sulfonamides with guanidine carbonate. The subsequentcondensation of these compounds (IV) with the Bdicarbonyl compounds (V)can be carried out, for example, by means of an alkali metal alcoholatein alcohol. The ,B-dicarbonyl compounds (V) are in this connection usedeither in free form or in the form of functional derivatives thereof,such as the acetals. They can, however, also be prepared in a one potprocess by the Vilsmeier method from aldehyde acetals, acid chloridesand dialkyl formamides. If, instead of the dialdehydes, there are usedthe appropriately substituted malonic acid esters or malonic aldehydesor their functional derivatves, then the hydroxyl groups in the 4-and/or 6-positions of the pyrimidine ring msut subsequently be replacedby chlorine as for example by treatment with an inorganic acid chloride,this chlorine being readily removed reductively with, for example, zincdust.

The acylation of the compounds (VI) is carried out in the usual maner,for example, by reaction with the appropriate acid halides oranhydrides, preferably in the presence of an acid acceptor, or bytreatment with reactive acid esters.

Preferred starting materials of general formula (VIII) are, inparticular, 2-halopyrimidines. They can be prepared, for example, by thereaction of 2-hyd-roxy-pyrimidines with excess phosphorous oxychloride.The condensation of the compounds (VIII) with the benzene-sulfonamides(VII) preferably takes place in the presence of a base, such aspotassium carbonate. Instead of the 2-halopyrimidines, the correspondingtrialkylamino-pyrimidines can also be reacted with the sulfonamides,with the formation of trialkylamines, to give the desiredbenzene-sulfonasnide-pyrimidines.

The reaction of the sulfonic acids (IX) with the 2-acetylamino-pyrimidines (X) is carried out, using Freudenbergs method,by heating in absolute methanol, the acetyl residue split off thereby,being distilled off in the form of the methyl ester.

The invention includes not only the compounds in their free form buttheir alkali salts as well. The salts are prepared in the conventionalmanner and preferably in the form of the sodium, potassium, and ammoniumsalts. Salt formation takes place byvirtue of the fact that the NH groupdirectly adjacent to the S group exhibits a strongly acid elfect due tothe vicinity of the said S0 group and therefore in an alkaline medium aproton is split off and the salt formed.

Salts of this type and particularly of sulfonyl ureas are known and havebeen described, for example, in Netherlands Pa'tent 6,411,087.

The following examples are given in order to more clearly disclose thenature of the present invention. It should be understood, however, thatthe examples are not intended to be a limitation on the scope of theinvention.

Example 1.-2- [4- fl-benzamido-ethyl) -benzenesulfonamido] -5-propoxy-pyrimidine 4 g., Z-amino-5-propoxy-pyrimidine and 17 g.benzamido-ethylbenzeneasulfochloride were added to 60 ml. methylenechloride. Trimethylamine was introduced into the resulting mixture, withstirring. After a reaction time of 15 minutes, solution had taken placeand thereafter the reaction product slowly separated out. Trimethylaminewas passed in for a further 1.5 hours. The precipitate was filtered offwith suction and heated for 1 hour on a water bath with ml. 10% sodiumhydroxide solution. The solution was subsequently neutralized withdilute hydrochloric acid, an oil thereby being formed. The supernatantwater was poured off and the remaining oil stirred with ethyl acetate.The 2-[4-(;8-benzamido-ethyl)benzene-sulfonamido]-5-propoxy-pyrimidinewhich was thereby formed crystallized out. Following recrystallizationfrom butanol, the 2-[4-(flbenzamido-ethyl)-benzene-sulfonamido]-5-propoxy-pyramidine melted at 194C.

The following compounds were prepared by an analogous procedure:

amido]-5-rnethoxyethoxy-pyrimidine; M.P. C.;

2 [4 ([3 benzamido ethyl) benzene sulfonylamido]-5-phenyl-pyrimidine;M.P. 230 C.;

2 [4 (B p chlorobenzamido ethyl) benzenesulfonylamido]-5-phenyl-pyrimidine; M.P. 228-230 C.;

2 [4 (B benzamido ethyl) benzenesulfonylamido]-S-(p-ehlorophenyl)pyrimidine; M.P. 230 C.;

Example 2.2- [4- p-benzamido-ethyl benzene-sulfonylamido] -5-rnethoxypyrimidine 4 g. 2-amino-5-methoxy-pyrimidine in 33 ml. absolutepyridine were reacted with 10.3 g. benzamido-ethylbenzene-sulfochloride,while stirring, the reaction mixture being cooled in a mixture of iceand salt. After 2 hours,

the reaction mixture was allowed to warm up to room temperature and thestirring continued for a further 5 hours. The reaction mixture wasallowed to stand overnight, and then it was heated to 100 C. for 1 hour.The heated mixture was evaporated in a vacuum and the residue stirredwith dilute hydrochloric acid in an ice bath. The acidic solution wasdecanted off and the residue dissolved in ammonia and reprecipitatedwith acetic acid. The2-[4(B-benzamido-ethyl-benzene-sulfonylamido]-5-methoxy-primidine thusobtained had a melting point of 198-200 C.

The following compounds were prepared in an analogous manner:

2 [4 (fl benzamido ethyl) S-butoxy-pyrimidine; M.P. lized frompropanol);

2 [4 (,8 benzamido ethyl) benzene sulfonamido] S-propyl-pyrimidine; M.P.207-208" C. (recrystallized from ethanol);

2 [(B p chlorobenzamido ethyl) benzenesulfonamido]-5-(fi-methoxy-ethoxy)-pyrimidine; M.P. 193 196 C.(recrystallized from ethanol),

2 [4 (,8 benzarnido ethyl) benzene sulfonamido]S-(B-ethoxy-ethoxy)-pyrimidine; M.P. 182 C. (recrystallized frompropanol);

2 [4 (B benzamido ethyl) benzene sulfonamido] S-ethoxy-pyrirnidine; M.P.22l-222 C. (recrystallized from glacial acetic acid);

2 [4 (48 benzamido methyl) benzene sulfonamibenzamido ethyl) benzenesulfonylbenzene sulfonamido] l96 C. (recrystaldo]-5-propyl-pyrimidine;M.P. 242 C. (purified by dissolving in ammonia and precipitating withhydrochloric acid);

2 [4 (B isovalerianylamido ethyl) benzene sulfonamidoJ-S-propylpyrimidine; M.P. 179-180 C. (recrystallized from ethanol);

2 [4 (fi benzamido ethyl) benzene sulfonamido] S-ethyl-pyrimidine; M.P.222 C. (recrystallized from ethanol);

2 [4 (fi benzamido ethyl) benzene sulfonamido] S-isobutyl-pyrimidine;M.P. 222 C. (recrystallized from ethanol);

2 [4 (B p chlorobenzamido ethyl benzenesulfonamido]15-n-propyl-pyrimidine; M.P. 227 C. (recrystallized fromglacial acetic acid);

2 [4 (,6 benzamido ethyl) benzene sulfonamido] S-n-butyl-pyrimidine;M.P. 181 C. (recrystallized from ethanol);

2 [4 ()9 benzamido ethyl) benzene sulfonamido] S-cyclohexyl-pyrimidine;M.P. 233 C. (recrystallized from ethanol);

2 [4 ([3 benzamido ethyl) benzene sulfonamido] 5-(3-pentyl)-pyrimidine;M.P. 176179 C. (recrystallized from ethanol);

2 [4 (t3 benzamido ethyl) benzene sulfonamido] S-benzyl-pyrimidine; M.P.20420,5 C. (recrystallized from ethanol);

2 [4 (,8 benzamido ethyl) benzene sulfonamido]S-(hexahydrobenzyl)-pyrimidine; M.P. 196 C. (recrystallized fromethanol).

Example 3 .2- [4- B-benzamido-ethyl-benzene-sulfonamido] -5-B-methoxy-ethoxy -pyrimidine 10 g. phosgene were introduced, withstirring and at a temperature of -5 C., into a solution of 7.3 g.dimethyl formamide in 50 ml. dry methylene chloride. 12.6 g. ,3-methoxy-ethoxy-acetaldehyde-dimethoxy-ethyl acetal were subsequentlyadded thereto dropwise. The reaction mixture was boiled for hours, whilestirring, then cooled, the pH adjusted to 8.0 using therefor a 2030%solution of sodium methylate, the salt filtered off with suction and thefiltrate evaporated in a vacuum on a water bath (temperature 60 C.). Theresidue was introduced dropwise, with stirring, into a boiling mixtureof 2.3 g. sodium in 50 ml. absolute ethanol and 17.3 g. 4-(5-benzamido-ethyl)-benzene-sulfonyl-guanidine (M.P. 265 C.; prepared from4-(B-benzamido-ethyl) benzene-sulfonamide by melting with guanidinecarbonate). The reaction mixture was boiled under reflux, whilestirring, for 5 hours and subsequently poured into water. Undissolvedmaterial was filtered off with suction, the filtrate acidified, thereaction product filtered oif with suction and recrystallized fromethanol. The 2-[4-(B benzamido-ethyl)-benzene sulfonamido] 5 (,8 methoxyethoxy) pyrimidine thereby obtained melted at 187 C.

The following compounds were also obtained in an analogous manner:

2 [4 (benzamido methyl) benzene sulfonarnido]5-(,8-methoxy-ethoxy)-pyrimidine; M.P. l95l97 C. from4-(benzamido-methyl)-benzene-sulfonyl-guanidine; M.P. 264-265 C.);

2 [4 (B acetylamido ethyl) benzene sul'fonamido} S-propyl-pyrimidine;M.P. 182183 C. (recrystallized from ethanol);

2 [4 ([3 benzamido ethyl) benzene sulfonamido-]- S-isopropyl-pyrimidine;M.P. 189 C. (recrystallized from propanol).

Example 4.2 [4 (B p chlorobenzamido ethyl)-benzene-sulfonamido]-5-butoxy-pyrimidine 1.4 g. 2- [4- ,B-amino-ethyl)-benzene-sulfonamido] -b-utoxy-pyrimidine (M.P. 223-225 C.) weredissolved in 2 ml. 2 N sodium hydroxide solution and mixed with 0.7 g.p-chlorobenzoyl chloride. The reaction mixture was stirred for 3 hoursat 40 C. A further 0.2 ml. 2 N sodium hydroxide solution and a further0.1 g. p-chfloro-benzoyl chloride were added thereto and heatingcontinued for another 2 hours. The reaction mixture was then filteredwith suction, the residue washed with ether and dis-solved in a solutionof sodium carbonate. Carbon was added to the lakaline solution which wasthen filtered. The filtrate was mixed with hydrochloric acid and2-[4-(fl-p-chlorobenzamido et'hyl) benzene sulfonamido] 5 butoxypydimidine precipitated out; M.P. 202 C. after recrystallization frommethanol.

In an analogous manner, 2-[4-(fl-hexahydrobenzamidoethyl) benzenesulfonamido] 5 propoxy pyrimidine was obtained from 2 (amino ethylbenzene sulfonamido) 5 propo-xy pyrimidine (M.P. 207-210 C.) andhexahydrobenzoyl chloride. This compound had a melting point of 219 C.after recrystallization from etha- 1101.

The following compounds were also obtained in an analogous manner:

2 [4 (B m toluylamido ethyl) benzene sulfonamido]-5-n-propyl-pyrimidine;M.P. 188190 C. (recrystallized from propanol);

2 [4 ((3 phenylmercapto acetamido ethyl) benzene sulfonarnido] 5 npropyl pyrimidine; M.P. l93194 C. (recrystallized from ethanol);

2 [4 ([3 In chlorobenzam'ido ethyl) benzenesulfonamido]-5-isobutyl-pyrimidine; M.P. 173 C. (recrystallized fromethanol);

2 [4 (B p methoxybenzam-ido ethyl) benzenesulifonamido]-5-isobutyl-pyrimidine; M.P. 216 C. (recrystallized fromethanol);

2 [4 (/3 o methoxy benzamido ethyl)benzenesulfonamido]-5-isobutyl-pyrimidinc; M.P. 157 C.; the compound wasisolated as the ammonium salt and recrystallized from water and the freecompound liberated by the addition of hydrochloric acid;

2 [4 (,8 m trifluoromethyl benzamido ethyl) benzene sulfonamido] 5isobutyl pyrimidine; M.P. 19 8-202 C. (purified by precipitation fromsolution in sodium carbonate by the addition of hydrochloric acid);

2 [4 (/3 hexahydrobenzamido ethyl) benzene sulfonamido] -'5isobutyl-pyrimidine; M.P. 186 C. (recrystallized from ethanol);

2 [4 (fl m methoxy benzamido ethyl) benzenesulfonamido] 5 isobutylpyridine; M.P. 148-150" C. (recrystallized from ethanol);

2 [4 (/3 m toluylamido ethyl) benzene sulfonamidol] 5 isobutylpyrimidine; M.P. -177 C. (recrystallized from ethanol);

2 [4 6 o toluylamido ethyl) benzene sulfonamido] 5 isobutyl pyrimidine;M.P. 159-1 6 0 C. (recrystallized from ethanol);

2 [4 8 m fluoro benzamido ethyl) benzene sulfonamido] 5 isobutylpyrimidine; M.P. 202-203 C. (recrystallized from ethanol);

2 [4 5 o ethoxy benzamido ethyl) benzene sulfonamido] 5 isobutylpyrimidine; M.P. 145-147 C. (recrystallized from ethanol);

2 [4 (B methox-y benzamido ethyl) benzene sulfonamido] 5 (2 butyl)pyrimidine; M.P. 144- 147 C. (recrystallized from ethanol);

2 [4 (/8 methoxy benzamido ethyl) benzene sulfonamido] 5 (3 methylbutyl) pyrimidine; M.P.

157-158 C. (recrystallized from ethanol);

2 [4 3 phenylmercapto acetamido ethyl) benzene sulfonamido] 5isobutyl-pyrimidine; M.P. 174 C. (recrystallized from ethanol);

2 [4 (B 2' naphthoylamido) ethyl benzene sulfonamido] 5 isobutylpyrimidine; M.P. 198 C. (recrystallized from ethanol);

2 [4 (B benzamido ethyl) benzene sulfonamido]- 5 (2 butyl) pyrimidine;M.P. 203205 C. (recrystallized from ethanol).

Example 5.2- [4-(fi-benzamido-eth'yl) -.benzenesulfonamido]-5-isobutyl-pyrimidine 0.95 g. of the sodium salt of4-(fl-benzamido-ethyl)- benzene-sulfonamide and 0.5 g.2-chloro-5-isobutyl-pyrimidine were slowly heated to 240 C. The twosubstances reacted during the melting and were kept for half an hour at220240 C. After cooling the reaction mixture was dissolved in a dilutedsodium hydroxide solution, filtered and precipitated with hydrochloricacid. The 2-[4- (,8 benzamido ethyl) benzene sulfonamido]isobutyl-pyrimidine was recrystallized from ethanol and melted at 217 C.(yield 39%).

In an analogous manner there was obtained 2-[4-(5-0- methoxy benzamidoisopropyl) benzene sulfonamido) 5 isobutyl pyrimidine; M.P. 142-144 C.(recrystallized from ethanol).

Example 6.-2- [4- B-benzoyl-N-methylamino-ethyl) benzene-sulfon amido]-5-isobutyl-pyrimidine 2 g. 2-amino-5-isobutyl pyrimidine were dissolvedin ml. anhydrous pyridine and mixed, with ice cooling, with 4.9 g. 4 (tibenzoyl N methylamino ethyl) benbene -sulfochloride (oil; prepared fromN methylaminoethyl-benzene by sulfochlor ination with chlorosulfonicacid). The reaction mixture was allowed to stand overnight and thenheated for one hour on a water bath. The reaction mixture was thenevaporated in a vacuum and the residue taken up in a mixture of dilutesodium carbonate solution and ammonia. The solution thus produced wasfiltered over charcoal and the filtrate acidified with hydrochloricacid. The precipitated substance was then recrystallized from alcohol.There was obtained 2-[4- (B benzoyl N methylamino ethyl) benzenesulfonamide]-5-isobutyl-pyrimidine having a melting point of 170172 C.

Example 7.2 [4 (B-T-methoxy-S'-chlorobenzoyl-N- methylaminoethyl)-benzene-sulfonamido]-5-isobutylpyrimidine 1.8 g.5-chloro-2-methoxybenzoyl chloride were added,

with stirring, to 3 g.2-[4-(fi-N-methylamino-ethyl)-benzene-sulfonamido]-5-isobutyl-pyrimidinein 13 ml. anhydrous pyridine and allowed to stand overnight. Thereaction mixture was then heated for one hour at 100 C.,

allowed to cool and poured on to ice. The precipitated material wasfiltered off with suction, taken up in a solution of sodium carbonateand again precipitated out with hydrochloric acid. The product wasfinally recrystallized from methanol. There was thereby obtained2-[4-(fi-2'- methoxy 5chlorobenzoyl-N-methylaminoethyl)-benzene-sulfonamido]-5-isobutyl-pyrimidinehaving a melting point of 186 C.

The following method was followed in the preparation of the startingmaterial:

15 g. 4 (,8 acetyl N-methylamino-ethyl)-benzener sulfonamide (preparedby the reaction of 4-(fi-acetyl-N- methylamino-ethyl)-benzene withchlorosulfonic acid and amidation of the sulfochloride obtained; M.P.l49-l50 C.) were mixed with 10 g. 2-chloro-5-isobutyl-pyrimidine and 8.1g. potassium carbonate and slowly heated up to 190200 C. After heatingfor two hours, the reaction mixture was allowed to cool and the melttaken up in water. The resulting solution was treated with animalcharcoal, filtered and the 2-[4-(B-acetyI-N-methylarninoethyl)benzene-sulfonamido]-5-isobutylpyrimidine which formed precipitated outby the addition of hydrochloric acid; M.P. 193194 C. 15.9 g. of thisacetyl compound were dissolved in 60 ml. 2 N sodium hydroxide solutionand boiled under reflux for 7 hours. The reaction mixture was thencooled and adjusted to pH 7 with 2 N hydrochloric acid. The 2-[4-({3-N-methylamino-ethyl) -benzenesulfonamido]-5-isobutyl-pyrimidineobtained in this manner melted at 2l32l5 C.

The following compounds were prepared in an analogous manner:

2 [4 (13-5'-methyl-2-methoxybenzoyl-N-methylaminoethyl) benzenesulfonamido]-5-isobutyl-pyrimidine; M.P. 147l49 C.;

2 [4 (,8-0-rnethoxybenzoyl-N-methylamino-ethyl)-ben- Cir 8 benesulfonamido] S-isobutyl-pyrimidine; M.P. 169- 170 C.; and 2 [4 (,8m-chlorobenzoyl-N-methylamino-ethyl)-benzene sulfonamide]S-isobutyl-pyrimidine; M.P. 174 176 C.

Example 8.2 [4 9 2-methoxy-5'-chlorobenzoyl-N- ethylarninoethyl) benzenesulfonamido1-5-isohutylv pyrimidine 1.7 g. S-chloro-Z-methoxy-benzoylchloride were added, with stirring, to 3 g.2-[4-(B-N-ethylamino-ethyl)-benzenesulfonamido]-S-isobutyl-pyrimidine in30 ml. anhydrous pyridine. The reaction mixture was then left to standovernight, subsequently heated to C. for one hour, allowed to cool andpoured onto ice. The precipitated material was filtered off withsuction, dissolved in a solution of sodium carbonate and precipitatedagain with hydrochloric acid. It was thereafter recrystallized twicefrom isopropanol. There was thusly obtained 2-[4-(fl-2'-methoxy 5'chlorobenzoyl N-ethylamino-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine having a melting point of 148-150 C.

The following method was used for the preparation of the startingmaterial:

10.4 g. 4 (B acetyl-N-ethylamino-ethyl)-benzene-sulfonamide (prepared bythe reaction of 4-( S-acetyI-N- ethyl-amino-ethyl)-benzene withchlorosulfonic acid and amidation of the sulfochloride so obtained; M.P.180- 18l C.) were mixed with 6.6 g. 2-chloro-5-isobutylpyrimidine and5.3 g. potassium carbonate and slowly heated up to 200 C. After heatingfor 2 hours, the reaction mixture was allowed to cool and the melt takenup in water. The solution was then treated with animal charcoal,filtered and the2-[4-[3-acetyl-N-ethylamino-ethylbenzene-sulfonamido]-5-isobutyl-pyrimidineformed precipitated out with hydrochloric acid; M.P. 168 C. The acetylcompound was subsequently heated for 8 hours with 3 mol 2 N sodiumhydroxide solution whereby 2-[4- (,8 N ethylamino ethylbenzene-sulfonamido]-5-isobutyl-pyrimidine; M.P. 238-240 C. was formed.

Example 9.2-[3-,3-m-fluorbenzamido-ethyl)-benzenesulfonamido}-isobutyl-pyrimidine 3 g. 3-(B-m-fiuorbenzamido-ethyl)-benzenesulfonamide was thoroughly mixed with 1.6 g.2-chlor-5-isobutylpyrimidine and 1.3 g. potassium carbonate and themixture thereafter heated in an oil bath for 3 hours at C. Followingcooling, the melt was taken up in dilute soda lye and the solutionextracted with ether. The alkaline solution was treated withhydrochloric acid and the precipitated material recovered andrecrystallized from acetic ester. Th 2 [3B-m-fluorbenzamido-ethyl)-benzene-sulfonamido]-isobutyl-pyrimidinethereby formed melted at 158 C.

- Example 10 A procedure analogous to that disclosed in Example 4 wasfollowed to produce the following compounds:

2 [4 (/8 3chlor-2-methoxy-benzamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine;melting point 171 C. (sodium salt recrystallized from water);

2 [4 (B 3 methyl-Z-methoxy-benzamido-ethyl)-benzenesulfonamido]-5-isobutylpyrimidine; M.P. 178- 179 C.(recrystallized from ethanol);

2 [4 (,8 5 methyl-Z-methoxy-benzamido-ethyl)-benzenesulfonamido] 5isobutyl-pyrimidine; M.P. 156- 157 C. (recrystallized from ethanol);

2 [4 (,6 5 brom-2-methoxy-benzamido-ethyl)-benzenesulfonamido] 5isobutyl-pyrimidine; M.P. 166- 167 C. (recrystallized from propanol);

2 [4 (ti 5,2 dimethoxy-benzamido-ethyl)-benzenesulfonamide] Sisobutyl-pyrimidine; M.P. 149152 C. (recrystallized from ethanol);

2 [4 ([3 5 fluor-2-methoxy-henzamido-ethyl)-benzenesulfonamide] 5isobutyl-pyrimidine; M.P. 172- 174 C. (recrystallized from ethanol);

2 [4 (,8 5 chlor-2-ethoxy-benzamido-ethyl)-benzene suifonamido] 5isobutyl-pyrimidine; M.P. 155l57 C. (recrystallized from ethanol).

Example 11.2-[4(,B-o-methoxy benzamido-ethyl)- benzene -sulfonamido] -5-pr opyl-pyrirnidine To a solution of 2 g.2-[4-(B-amino-ethyl)-benZene-sulfonamido]-5-propyl-pyrimidine in 6 ml.pyridine 1 ml. of o-methoxy-benzylochloride was added. The reactionmixture was left at room temperature for 12 hours and then heated for /2hour on a water bath. After cooling, the reaction mixture was poured onice and acidified by means of hydrochloric acid. The precipitate wasfiltered off with suction and thereafter dissolved in an aqueous sodiumcarbonate solution. Carbon was added to the alkaline solution which wasthen filtered. The filtrate was acidified by means of hydrochloric acidand 2-[4-(fl-o-methoxy-benzamido-ethyD-benzenesulfonarnido]-5-propyl-pyrimidine was obtained in 70% yield; M.P. 174 C.

The following compounds were also obtained in an analogous manner:

2-[4-(5 phenoxy-acetamido-ethyD-benzene-sulfonamido]-S-isObutyI-pyrimidine; M.P. 166-170 C. (recrystallized from ethanol);

2-[4-(fi-2,6-dimethoxybenzamido-ethyl)-benzene-sulfonamido]-5-isobutyl-pyrimidine; M.P.170-171 C. (recrystallized from ethanol);

2-[4-(B-o-methoxy benzamidoethyl)-benzene-sulfonamido]-5-isobutoxy-pyrimidine; M.P. 192-195 C.(recrystallized from a mixture of methanol and dimethylform amide)2-[4-(,8-2-meth-oxy-5-chloro benzamidoethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine; M.P. 166l67 C.(purified by precipitation from a solution in sodium carbonate byaddition of hydrochloric acid).

The blood sugar reducing activities of some of the new2-'benzene-sulfonamido-pyrimidines were compared with that of the knowncompounds, i.e., the 2-benzene-sulfonamido-5-methoxy-ethoxy-pyrimidine,N -sulfanilyl-N -(n butyD-urea and N p toluene sulfonyl)-N -(n-butyl)-urea. The blood sugar reducing activity was measured in the rabbitfollowing i.v. administration of the test compounds. The data set out inTable I which follows represent those compounds having the relativeblood sugar reducing activity of at least 80 compared to the blood sugarreducing activity of N -sulfanilyl-N -(n-bu'tyl)-urea. The increase inactivity of the compounds of the invention as compared to N -(p-toluenesulfonyl)-N -(n-butyl)-'urea amounted to at least 8-fold, the latterbeing the case also in the comparison experiments with2-benzene-sulfonamido-S-methoxyethoxy pyrimidine. The most effectivecompounds of the invention which were employed in testing, i.e., 1

2-[4- (fl-benzamido-ethyl) -benzene-sulfonamido]-5-isobutyl-pyrimidine,

2- [4- S-m-chlorobenzamido-ethyl) -'benzene-sulfon amido] 5-isobutyl-pyrimidine,

2- [4-( 3-o-met-hoxybenzamido-ethyl)benzene-sulfonamido]-5-isobutyl-pyrimidine, and

2- [4- (fi-m-trifluorornethyl-benzamido-ethyl) -benzene-sulfonamido]-5-isob-utyl-pyrimidine,

2- 4- (fl-o-ethoxy benzamido-ethyl) -benzene-sulfonamido]-5-isobutyl-pyrimidine,

2-[4- (,B-o-methoxybenzamido-ethyl -b enzene-sulfonamido] -5-3-methyl-butyl -pyrimidine,

2- [4 (fi-Z-methoxy-S-chloro-benzamido-ethyl) benzenesulfon amido]-5-isobutyl-pyrimidine,

2- [4-(5-5-methyl-2-methoxy-benzamido-ethyl) -'benzenesulfonarnido]-5-isobutyl-pyrimidine,

2- [4- (fl-S-bromo 2-rnethoxy benzamido-ethyl) -benzenesulfonamido]-5-isobutyl-pyrimidine,

2- 4- (B-5,2-dimethoxy-benzamido-ethyl) -benzene-su1fonamido]-5-isobutyl-pyrimidine,

2-[=4-(,B-S-fluoro-2-methoxy-benzamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine,and

2-[4- (,8-5-chl0ro-2-ethoxy-benzamido-ethyl-benzenesulfonamido]-5-isobutyl-pyrimidine,

demonstrated activity amounting to at least 40 times that of the 2benzene-sulfonamido-S-methoxy-ethoxy-pyrimidine.

The therapeutic range of the above compounds is particularly great asthe acute toxicity as measured in the mouse resulted in an LD (S.C.) ofabout 1.24.6 g./kg. which is very slight. The therapeutic range for theproducts of the invention is particularly great as compared withcomparison compounds.

The effective threshold dose for 2-[4-( 8-o-methoxybenzamido-ethyl)benzene sulfonamido]-5-isobutyl-pyrimidine was determined in the rabbitand via the i.v. route amounted to 0.1 mg./kg. For oral administration,the effective threshold dose similarly amounted to 0:1 mg./kg. (bloodsugar decrease of 15-20%). In the extended time experiments, 2.5 mg./kg.i.v. in the rabbit was effective for at least 22 hours. In the dog, 0.1mg/kg. both i.v. and oral was effective to produce a decrease in bloodsugar. The effective threshold dose for 2-[4-(fi-2-ethoxy-5-chlorobenzamido-ethyl) benzene sulf0namido]-5-isobutyl-pyrimidinewas determined in the rabbit and via the i.v. route amounted to 0.0125mg./kg. For oral administration the effective threshold dose of2-[4-(B-2-metlhoxy-5-chlorobenzamido-ethyl) benzenesulfonamido]-5-isobutyl-pyrimidine amounted to 0.05 mg./kg.

TABLE I Relative Blood LD50 s.c. No. Sugar Reducing Mouse,

Aetivityg./kg. Rabbit, i.v.

2-[4-(13-benzamido-ethyl)-benzenegulfonamido1-5-propoxy pyrimi- 802-[4-(B-p-chlorobenzamido-ethyl) benzene-sulfonamido]5-phenylpyrimidine.

2-[4-(fl-hexahydro-benzamido-ethyl)-benzene-Sulfonamido]-5-pr0poxypyrimidine.

2-[4-(B-henzamido-ethyl) -benzenesullonamido]-5-propyl-pyrimidine.

2-[4- (B-benzamido-ethyl) -benzcriesulfonamidoI-fi-iso-butyl-pyrimime.2-[4-(6-bcnzamido-ethyl) benzenesulfonamido]-5-benzyl-pyrimidine.2-[4-(fl-m-methoxybenzamido-ethyl)benzene-sulfonamido]-5-is0butylpyrimidine.2-[4-(5-2-methoxy-5-chlorobenzoyl- N-meth ylamino-ethyl) -benzenesulfonamido]-5-isobutyl-pyrimime. 4002-[4-(B-2-methoxy-5-ch1orobenz0yl- N -ethyl-aminoethyl)-benzenesulfonamido]-5-isobutyl-pyrimi- 2, 0002-[4-(5-0-othoxybenzamido-ethyl)-benzene-sulfonarnido]-5-isobutylyrirnidine.

2- 4-(fl-o-methoxy-benzamido-ethyl)benzene-sulfonamido1-5-(3-methylbutyl) -pyrimidine.

2-[4-(fl-2-n1ethoXy-5-chloro-benzami- (lo-ethyl)-benzene-sulfonamido]-5-isobutyl-pyrimidine.

2-[4-(B-5-rnethyl-2-rnethoxy-benzamido-ethyl) -benzen e-sulfoua1ni lo]fi-isobutyl-pyrimidine.

TABLE I-Cntinued Relative Blood LD s.c.- No. Sugar Reducing Mouse,

et (airy-pyrimidine.

In normal clinical use, the compounds can be employed in both the freeand the salt form. The activity of the compounds is independent ofwhether they are in salt form or otherwise. Salts may be prepared by anyof the well-known standard methods. While the salt normally employed isthe alkali salt and preferably the sodium salt, the compounds have beenprepared in the form of other salts, such as potassium, ammonium, etc.

The products of this process may be combined with a pharmaceuticalcarrier for administration to humans in an amount to attain the desiredblood sugar reducing effect. Such carriers are either solid or liquid.Exemplary of solid pharmaceutical carriers are lactose, cornstarch,mannitol, talc, etc. The compounds of this invention are mixed with acarrier and filled into hard gelatin capsules or tabletted with suitabletabletting aids, such as magnesium stearate, starch, or otherlubricants, disintegrants or coloring agents. If combination with aliquid carrier is desirable, a soft gelatin capsule is filled with aslurry or other dispersion of the novel compounds in soya-bean, corn orpeanut oil. Aqueous suspensions or solutions are prepared for alternate,oral or parenteral administration.

The dosage of the novel compounds of the present invention for thetreatment of diabetes depends in the main on the age, weight, andcondition of the patient being treated. The preferable form ofadministration is via the oral route in connection with which dosageunits containing -500 mg. of active compound in combination with asuitable pharmaceutical diluent is employed. One or two unit dosages aregood from one to four times a day.

We claim:

1. A compound selected from the group consisting of2-benzene-sulfonamido-pyrirnidines of the formula:

wherein X is alkylene containing from 1 to 4 carbon atoms, A is a memberselected from the group consisting of substituted or unsubstituted alkylhaving 1 to 5 carbon atoms wherein said substituent is a member selectedfrom the group consisting of phenoxy and phenylmercapto; cyclohexyl andsubstituted or unsubstituted benzyl, toluyl and naphthyl wherein saidsubstituent is from 1 to 3 members selected from the group consisting ofhalogen, lower alkyl, trifluoromethyl and lower alkoxy, R is a memberselected from the group consist ing of alkyl having 1 to 5 carbon atoms,alkoxy having up to 4 carbon atoms, benzyl, hexahydrobenzyl, phenyl,

12 chlorophenyl and cyclohexyl and R is a member selected from the groupconsisting of hydrogen, lower alkyl having 1 to 3 carbon atoms and thepharmaceutically acceptable alkali salts thereof.

2. A compoundaccording to claim 1 designated 2-[4- (fl-oethoxybenzamidoethyl) benzenesulfonamidoll 5- isobutyl-pyrimidine or thepharmaceutically acceptable alkali salt thereof. 7 3. A compoundaccording to claim 1 designated 2-[4- (,8-o-methoxybenzamido-ethyl)benzenesulfonamido1-5- (3-methylbutyl)-pyrimidine or thepharmaceutically acceptable alkali salt thereof.

4. A compound according to claim 1 designated 2-[4-(p-Z-methoxy-S-chloro-benzamido-ethyl)benzenesulfonamido]-5-isobutyl-pyrimidine or the pharmaceuticallyacceptable alkali salt thereof.

5. A compound according to claim 1 designated 2-[4-(fl-o-methoxybenzamido-ethyl) benzenesulfonamido1-5-(3-methylbutyl)-pyrimidine or the pharmaceutically acceptable alkalisalt thereof.

6. A compound according to claim 1 designated 2-[4-(,B-S-methyl-Z-methoxy benzamido-ethyl)benzenesulfonarnido]-5-isobutyl-pyrimidine or the pharmaceuticallyacceptable alkali salt thereof.

7. A compound according to claim 1 designated 2-[4- (B-S-bromo-Z-methoxybenzamido-ethyl) benzenesulfonamido]-5-isobutyl-pyrimidine or thepharmaceutically acceptable alkali salt thereof.

8. A compound according to claim 1 designated 2-[4- (5-52 dimethoxybenzamido-ethyl) benzenesulfonamido]-5-isobutyl pyrimidine or thepharmaceutically acceptable alkali salt thereof.

9. A compound according to claim 1 designated 2-[4-(fi-S-lluor-Z-rnethoxy benzamido-ethyl)benzenesulfonamido]-5-isobutyl-pyrimidine or the pharmaceuticallyacceptable alkali salt thereof.

10. A compound according to claim 1 designated 2-[4-(fl-5-chlor0-2-ethoxy benzamido-ethyl)benzene-sulfonamido]-5-isobutyl-pyrimidine or the pharmaceuticallyacceptable alkali salt thereof.

11. A compound according to claim 1 wherein R represents alkyl having3-5 carbon atoms, R represents hydrogen, X represents (CH and Arepresents wherein Y is a member selected from the group consisting ofhydrogen, alkyl and alkoxy having 13 carbon atoms and X is alkoxy having13 carbon atoms and the pharmaceutically acceptable alkali saltsthereof.

References Cited UNITED STATES PATENTS 3,198,706 8/1965 Ruschig et al.l6765 3,275,635 9/1966 Priewe et al. 16765 OTHER REFERENCES Netherlandsapplication, 641l,087, March 1965. 65.

ALEX MAZEL, Primary Examiner. R. GALLAGHER, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,377,351 April 9 1968 Erich Haack et al It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 3, line 38, "derivatves" should read derivatives line 39, "msut"should read must Column 4, line 52 and Column 5, lines 10 and 29,"ethyl", each occurrence, should read ethyl) Column 4, line 63, afterinsert 4- Column 6, line 3, "lakaline" should read alkaline lines 5 and6, "pydimidine" should read H pyrimidine line 43, "pyridine" should readpyrimidine Column 7, lines 16 and 17, "benbene" should read benzeneColumn 8, line 1, "bene" should read zene line 4, "sulfonamide" shouldread sulfonamido Column 9, line 9, "benzylochloride" should readbenzoylchloride Column 11, TABLE I-Continued, third column, line 13thereof, "be zene" should read benzene same column, line 14 thereof, "etoxy" should read ethoxy Column 12, line 6, benzenesulfonamidol" shouldread benzenesulfonamido Signed and sealed this 9th day of September1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

